Physiological activities of retinoic acid are known to be induced by the adjustment of various gene expressions via a transcriptional control mechanism mediated by a nuclear receptor, i.e., retinoic acid receptor (hereinafter referred to as “RAR”). On the other hand, it is reported that high retinoid level conditions lead to a series of side effects, so-called retinoic acid syndrome, such as skin disorders, headaches, fatigue, and teratogenicity during pregnancy.
In malignant tumor patients, the amount of retinoic acid in the blood is reduced. Reduced physiological functions of retinoic acid are known to be associated with carcinogenesis, and the growth and progression of cancer. For this reason, extensive research has been conducted so far on compounds that have RAR agonistic activity and are hopefully useful for antitumor agents. For example, natural retinoic acid in nature: All-trans retinoic acid (hereinafter referred to as “ATRA”) or metabolites thereof reportedly have physiological functions such as differentiation-inducing effects, and have a preventive effect on cancer; in addition, they are known as a treating agent for some diseases such as leukemia (Non-Patent Document 1). In recent years, among synthetic compounds other than ATRA, a compound group has been reported to have agonistic activity against RAR (collectively referred to as retinoids). Such compounds are expected to be used as pharmaceuticals.
RAR is known to be divided into three subtypes of α, β, and γ, which have different expression states depending on cell species and tissues, controlling various vital functions. Among these types, RARα is involved in cancer cell differentiation-inducing activity, cell-cycle arrest activity, apoptosis induction activity, etc. (Non-Patent Document 2); RARβ is involved in teratogenicity (Non-Patent Document 3); and RARγ is involved in skin toxicity, bone toxicity, etc. (Non-Patent Document 4). Accordingly, a retinoid with high RARα selectivity enhances antitumor effects and alleviates side effects induced by RARγ, thereby boosting clinical profits.
4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid (hereinafter referred to as “TAC-101”) is a retinoid that has RARα transcription-activating activity and cancer cell differentiation-inducing activity. Such a retinoid is known to be effective as antitumor agents, cancer cell differentiation-inducing agents, cancer metastasis inhibitors, therapeutic agents for diseases associated with angiogenesis, therapeutic agents for cardiac hypertrophy, etc. (e.g., Patent Documents 1 and 2). For example, TAC-101 has currently been under clinical development as orally-available antitumor agents. In a phase I study of non-small cell lung cancer, complete remission cases were reported, while symptoms (skin disorders) similar to hypervitaminosis A were observed (Non-Patent Document 5).
As stated above, it is desired to develop a retinoid that has high RARα selectivity and is hardly bonded with RARγ; in the clinical view, a pharmaceutical that has fewer side effects, such as skin disorders, and exerts a high antitumor effect.
Patent Document 1: Japanese Unexamined Patent Publication No. 1990-247185
Patent Document 2: International Publication No. WO 96/32101
Non-Patent Document 1: Journal of Clinical Oncology, 1992, May; 10(5), 839-864. Review.
Non-Patent Document 2: Blood. 1996 Mar. 1; 87(5), 1939-1950
Non-Patent Document 3: Development, 1991, November; 113(3), 723-734
Non-Patent Document 4: Am. J. Physiol., 1995, July; 269, E91-E98
Non-Patent Document 5: Journal of Clinical Oncology, Vol. 20, No. 16, 2002, 3522-3532